Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop.

Published

Journal Article

Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress.

Full Text

Duke Authors

Cited Authors

  • Oliver, TG; Meylan, E; Chang, GP; Xue, W; Burke, JR; Humpton, TJ; Hubbard, D; Bhutkar, A; Jacks, T

Published Date

  • July 8, 2011

Published In

Volume / Issue

  • 43 / 1

Start / End Page

  • 57 - 71

PubMed ID

  • 21726810

Pubmed Central ID

  • 21726810

Electronic International Standard Serial Number (EISSN)

  • 1097-4164

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2011.06.012

Language

  • eng

Conference Location

  • United States